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Abstract Understanding the neural basis of behavior requires monitoring and manipulating combinations of physiological elements and their interactions in behaving animals. We developed a thermal tapering process enabling fabrication of low-cost, flexible probes combining ultrafine features: dense electrodes, optical waveguides, and microfluidic channels. Furthermore, we developed a semi-automated backend connection allowing scalable assembly. We demonstrate T-DOpE (Tapered Drug delivery, Optical stimulation, and Electrophysiology) probes achieve in single neuron-scale devices (1) high-fidelity electrophysiological recording (2) focal drug delivery and (3) optical stimulation. The device tip can be miniaturized (as small as 50 µm) to minimize tissue damage while the ~20 times larger backend allows for industrial-scale connectorization. T-DOpE probes implanted in mouse hippocampus revealed canonical neuronal activity at the level of local field potentials (LFP) and neural spiking. Taking advantage of the triple-functionality of these probes, we monitored LFP while manipulating cannabinoid receptors (CB1R; microfluidic agonist delivery) and CA1 neuronal activity (optogenetics). Focal infusion of CB1R agonist downregulated theta and sharp wave-ripple oscillations (SPW-Rs). Furthermore, we found that CB1R activation reduces sharp wave-ripples by impairing the innate SPW-R-generating ability of the CA1 circuit. 

A conventional optical lens can be used to focus light into the target medium from outside, without disturbing the medium. The focused spot size is proportional to the focal distance in a conventional lens, resulting in a tradeoff between penetration depth in the target medium and spatial resolution. We have shown that virtual ultrasonically sculpted gradient-index (GRIN) optical waveguides can be formed in the target medium to steer light without disturbing the medium. Here, we demonstrate that such virtual waveguides can relay an externally focused Gaussian beam of light through the medium beyond the focal distance of a single external physical lens, to extend the penetration depth without compromising the spot size. Moreover, the spot size can be tuned by reconfiguring the virtual waveguide. We show that these virtual GRIN waveguides can be formed in transparent and turbid media, to enhance the confinement and contrast ratio of the focused beam of light at the target location. This method can be extended to realize complex optical systems of external physical lenses and in situ virtual waveguides, to extend the reach and flexibility of optical methods.